Vol 26, No 5 (2019)
Original articles — Basic science and experimental cardiology
Published online: 2018-04-25

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Effect of LCZ696, a dual angiotensin receptor neprilysin inhibitor, on isoproterenol-induced cardiac hypertrophy, fibrosis, and hemodynamic change in rats

Toru Miyoshi1, Kazufumi Nakamura1, Daiji Miura2, Masashi Yoshida1, Yukihiro Saito1, Satoshi Akagi1, Yuko Ohno3, Megumi Kondo1, Hiroshi Ito1
Pubmed: 29718530
Cardiol J 2019;26(5):575-583.

Abstract

Background: Recent clinical studies have shown that treatment with LCZ696, a complex containing the angiotensin receptor blocker valsartan and neprilysin inhibitor sacubitril, improves the prognosis of heart failure patients with a reduced ejection fraction. This study evaluated whether LCZ696 affects left ventricular hypertrophy, fibrosis, and hemodynamics in isoproterenol (ISO)-treated rats compared with valsartan alone.

Methods: Male Wistar rats received subcutaneous saline (n = 10), subcutaneous ISO (2.4 mg/kg/day; n = 10), subcutaneous ISO + oral LCZ696 (60 mg/kg/day; n = 20) (ISO-LCZ), or subcutaneous ISO + oral valsartan (30 mg/kg/day; n = 20) (ISO-VAL) for 7 days.

Results: LCZ696 and valsartan did not significantly reduce the increased heart weight/body weight ratio in rats treated with ISO. Echocardiography showed that the deceleration time shortened by ISO was restored by LCZ696 but not valsartan alone (p = 0.01 vs. the ISO group). Histological analysis showed that cardiac interstitial fibrosis increased by ISO was decreased significantly by LCZ696 but not valsartan alone (control: 0.10 ± 0.14%; ISO: 0.41 ± 0.32%; ISO-LCZ: 0.19 ± 0.23% [p < 0.01 vs. the ISO group]; ISO-VAL: 0.34 ± 0.23% [p = 0.34 vs. the ISO group]). Quantitative polymerase chain reaction showed that mRNA expression of Tgfb1, Col1a1, Ccl2, and Anp increased by ISO was significantly attenuated by LCZ696 but not valsartan alone (p < 0.05 vs. the ISO group).

Conclusions: LCZ696 improves cardiac fibrosis, but not hypertrophy, caused by continuous exposure to ISO in rats.

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References

  1. Lazzeroni D, Rimoldi O, Camici PG. From left ventricular hypertrophy to dysfunction and failure. Circ J. 2016; 80(3): 555–564.
  2. Bursi F, Weston SA, Redfield MM, et al. Systolic and diastolic heart failure in the community. JAMA. 2006; 296(18): 2209–2216.
  3. Cleland J, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006; 27(19): 2338–2345.
  4. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003; 362(9386): 777–781.
  5. Massie BM, Carson PE, McMurray JJ, et al. I-PRESERVE Investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008; 359(23): 2456–2467.
  6. Zois NE, Bartels ED, Hunter I, et al. Natriuretic peptides in cardiometabolic regulation and disease. Nat Rev Cardiol. 2014; 11(7): 403–412.
  7. Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol. 2010; 50(4): 401–414.
  8. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012; 380(9851): 1387–1395.
  9. McMurray J, Packer M, Desai A, et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med. 2014; 371(11): 993–1004.
  10. Sumita Yoshikawa W, Nakamura K, Miura D, et al. Increased Passive Stiffness of Cardiomyocytes in the Transverse Direction and Residual Actin and Myosin Cross-Bridge Formation in Hypertrophied Rat Hearts Induced by Chronic ^|^beta;-Adrenergic Stimulation. Circulation Journal. 2013; 77(3): 741–748.
  11. Miyoshi T, Nakamura K, Yoshida M, et al. Effect of vildagliptin, a dipeptidyl peptidase 4 inhibitor, on cardiac hypertrophy induced by chronic beta-adrenergic stimulation in rats. Cardiovasc Diabetol. 2014; 13: 43.
  12. Chen C, Rodriguez L, Levine RA, et al. Noninvasive measurement of the time constant of left ventricular relaxation using the continuous-wave Doppler velocity profile of mitral regurgitation. Circulation. 1992; 86(1): 272–278.
  13. Gallego B, Arévalo MA, Flores O, et al. Renal fibrosis in diabetic and aortic-constricted hypertensive rats. Am J Physiol Regul Integr Comp Physiol. 2001; 280(6): R1823–R1829.
  14. Takemoto M, Egashira K, Tomita H, et al. Chronic Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade : Effects on Cardiovascular Remodeling in Rats Induced by the Long-term Blockade of Nitric Oxide Synthesis. Hypertension. 1997; 30(6): 1621–1627.
  15. von Lueder TG, Wang BH, Kompa AR, et al. Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy. Circ Heart Fail. 2015; 8(1): 71–78.
  16. Suematsu Y, Miura SI, Goto M, et al. LCZ696, an angiotensin receptor-neprilysin inhibitor, improves cardiac function with the attenuation of fibrosis in heart failure with reduced ejection fraction in streptozotocin-induced diabetic mice. Eur J Heart Fail. 2016; 18(4): 386–393.
  17. Kusaka H, Sueta D, Koibuchi N, et al. LCZ696, Angiotensin II Receptor-Neprilysin Inhibitor, Ameliorates High-Salt-Induced Hypertension and Cardiovascular Injury More Than Valsartan Alone. Am J Hypertens. 2015; 28(12): 1409–1417.
  18. Biala A, Finckenberg P, Korpi A, et al. Cardiovascular effects of the combination of levosimendan and valsartan in hypertensive Dahl/Rapp rats. J Physiol Pharmacol. 2011; 62(3): 275–285.
  19. Grimm D, Holmer SR, Riegger GA, et al. Effects of beta-receptor blockade and angiotensin II type I receptor antagonism in isoproterenol-induced heart failure in the rat. Cardiovasc Pathol. 1999; 8(6): 315–323.
  20. Al-Mazroua HA, Al-Rasheed NM, Korashy HM. Downregulation of the cardiotrophin-1 gene expression by valsartan and spironolactone in hypertrophied heart rats in vivo and rat cardiomyocyte H9c2 cell line in vitro: a novel mechanism of cardioprotection. J Cardiovasc Pharmacol. 2013; 61(4): 337–344.
  21. Suematsu Y, Jing W, Nunes A, et al. LCZ696 (Sacubitril/Valsartan), an Angiotensin-Receptor Neprilysin Inhibitor, Attenuates Cardiac Hypertrophy, Fibrosis, and Vasculopathy in a Rat Model of Chronic Kidney Disease. J Card Fail. 2018; 24(4): 266–275.
  22. Jing W, Vaziri ND, Nunes A, et al. LCZ696 (Sacubitril/valsartan) ameliorates oxidative stress, inflammation, fibrosis and improves renal function beyond angiotensin receptor blockade in CKD. Am J Transl Res. 2017; 9(12): 5473–5484.
  23. Polhemus DJ, Trivedi RK, Gao J, et al. Renal Sympathetic Denervation Protects the Failing Heart Via Inhibition of Neprilysin Activity in the Kidney. J Am Coll Cardiol. 2017; 70(17): 2139–2153.
  24. Fujii M, Wada A, Ohnishi M, et al. Endogenous bradykinin suppresses myocardial fibrosis through the cardiac-generated endothelin system under chronic angiotensin-converting enzyme inhibition in heart failure. J Cardiovasc Pharmacol. 2004; 44 Suppl 1: S346–S349.
  25. Sato M, Engelman RM, Otani H, et al. Myocardial protection by preconditioning of heart with losartan, an angiotensin II type 1-receptor blocker: implication of bradykinin-dependent and bradykinin-independent mechanisms. Circulation. 2000; 102(19 Suppl 3): III346–III351.
  26. Seki T, Goto K, Kansui Y, et al. Angiotensin II receptor-neprilysin inhibitor sacubitril/valsartan improves endothelial dysfunction in spontaneously hypertensive rats. J Am Heart Assoc. 2017; 6(10).